INCB050465 (Parsaclisib), a Novel Next-Generation Inhibitor of Phosphoinositide 3-Kinase Delta (PI3Kδ)

Article abstract of DOI:10.1021/acsmedchemlett.9b00334

A medicinal chemistry effort focused on identifying a structurally diverse candidate for phosphoinositide 3-kinase delta (PI3Kδ) led to the discovery of clinical candidate INCB050465 (20, parsaclisib). The unique structure of 20 contains a pyrazolopyrimidine hinge-binder in place of a purine motif that is present in other PI3Kδinhibitors, such as idelalisib (1), duvelisib (2), and INCB040093 (3, dezapelisib). Parsaclisib (20) is a potent and highly selective inhibitor of PI3Kδwith drug-like ADME properties that exhibited an excellent in vivo profile as demonstrated through pharmacokinetic studies in rats, dogs, and monkeys and through pharmacodynamic and efficacy studies in a mouse Pfeiffer xenograft model.

Full text of DOI:10.1021/acsmedchemlett.9b00334

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Letter
INCB050465 (Parsaclisib), a Novel Next-Generation
Inhibitor of Phosphoinositide 3-Kinase Delta (PI3K#)
Eddy W Yue, Yun-Long Li, Brent Douty, Chunhong He, Song Mei, Brian Wayland, Thomas
Maduskuie, Nikoo Falahatpisheh, Richard B. Sparks, Padmaja Polam, Wenyu Zhu, Joseph
Glenn, Hao Feng, Ke Zhang, Yanlong Li, Xin He, Kamna Katiya, Maryanne Covington, Patricia
Feldman, Niu Shin, Kathy He Wang, Sharon Diamond, Yu Li, Holly K Koblish, Leslie Hall, Peggy
Scherle, Swamy Yeleswaram, Chu-Biao Xue, Brian Metcalf, Andrew P Combs, and Wenqing Yao
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.9b00334 • Publication Date (Web): 17 Oct 2019
Downloaded from pubs.acs.org on October 20, 2019
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INCB050465 (Parsaclisib), a Novel Next-Generation Inhibitor of
Phosphoinositide 3-Kinase Delta (PI3K)
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Eddy W. Yue,* Yun-Long Li,a Brent Douty, Chunhong He, Song Mei, Brian Wayland,b Thomas
Maduskuie, Nikoo Falahatpisheh, Richard B. Sparks, Padmaja Polam, Wenyu Zhu, Joseph Glenn, Hao
Feng, Ke Zhang, Yanlong Li, Xin He, Kamna Katiyar, Maryanne Covington, Patricia Feldman, Niu
Shin, Kathy He Wang, Sharon Diamond, Yu Li, Holly K. Koblish, Leslie Hall, Peggy Scherle, Swamy
Yeleswaram, Chu-Biao Xue, Brian Metcalf, Andrew P. Combs, and Wenqing Yao
Incyte Research Institute, Incyte Corporation, 1801 Augustine Cut-Off, Wilmington, Delaware 19803, United States
ABSTRACT: A medicinal chemistry effort focused on identifying a structurally diverse candidate for phosphoinositide 3-kinase
delta (PI3K led to the discovery of clinical candidate INCB050465 (20, parsaclisib). The unique structure of 20 contains a
pyrazolopyrimidine hinge-binder in place of a purine motif that is present in other PI3K inhibitors, such as idelalisib (1), duvelisib
(2), and INCB040093 (3, dezapelisib). Parsaclisib (20) is a potent and highly selective inhibitor of PI3K with drug-like ADME
properties that exhibited an excellent in vivo profile as demonstrated through pharmacokinetic studies in rats, dogs, and monkeys and
through pharmacodynamic and efficacy studies in a mouse Pfeiffer xenograft model.
KEYWORDS: Parsaclisib, INCB050465, PI3K, phosphoinositide 3-kinase delta, dezapelisib, INCB040093
aDeceased 4/20/2016
bDeceased 5/27/2018
Phosphoinositide 3-kinase delta (PI3K) is a lipid kinase that
phosphorylates the D-3 position of the inositol ring of
phosphoinositides.1 By acting as a downstream mediator of
signaling from receptor tyrosine kinases, including the B-cell
receptor, Toll-like receptors, and cytokine receptors,2 PI3K
plays a primary role in PI3K-AKT-mTOR pathway activation.
When dysregulated, PI3K can lead to the development of
hematologic malignancies including acute myeloid leukemia3
and chronic lymphocytic leukemia.4 PI3K is also central in
the regulation of immune cell function (e.g., B cells, T cells,
neutrophils, and mast cells),2,5 and PI3K activation therefore
may promote B-cell malignancies via both direct tumor and
immunomodulatory mechanisms. Importantly, by the same
virtue, PI3K is also garnering interest as a therapeutic target in
inflammatory respiratory diseases (e.g., chronic obstructive
pulmonary disorder, asthma), autoimmune diseases (e.g.,
systemic lupus erythematosus, rheumatoid arthritis, type 1
diabetes), and activated PI3K syndrome.2,6,7 As such, there are
currently intense efforts towards identifying inhibitors of PI3K
to treat hematologic malignancies as well as other cancers and
immunologic diseases.
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INCB050465 (20, parsaclisib), a highly potent and selective
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PI3K inhibitor that is currently in clinical trial studies for
diffuse large B-cell lymphoma (DLBCL),16 follicular
lymphoma,17 marginal zone lymphoma,18 and mantle cell
lymphoma.19 Described herein are the obstacles that were
encountered and the solutions that were found which eventually
led to 20.
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Figure 2. Design of quinoline and cinnoline inhibitors 4-6.
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One of the first ideas examined was to create a new core by
breaking the thiazole ring of 3 and forming a new 6,6-bicyclic
heterocycle (Figure 2) while maintaining the purine hinge-
binder that was needed for PI3K potency. The nitrogen in the
quinoline ring (4) was designed to replace binding pocket
interactions from the carbonyl oxygen of 3. The synthesis of
this purine series provided analogs that were either racemic or
scalemic. For all single isomer compounds, the stereogenic
center was assigned to be the same stereochemistry as C-1' of 3
(the opposite enantiomer was known to be inactive). The
stereochemistry of 3 was assigned S based on the X-ray crystal
structure data of an intermediate (unpublished data). Quinoline
4 was significantly less active compared with 3 (Table 1). It
was hypothesized that potency could be restored by introducing
small lipophilic groups at the 5-position of the quinoline ring to
mimic the removed thiazole ring. In particular, chloro-
Figure 1. Structures of idelalisib (1), duvelisib (2),
INCB040093 (3, dezapelisib), and INCB050465 (20,
parsaclisib).
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The first PI3K-selective inhibitor, idelalisib (1), was
approved for the treatment of hematologic malignancies (Figure
1).8,9 More recently, duvelisib (2), an inhibitor of both PI3K
and PI3K, was also approved for the same indications.10 The
efforts at Incyte to find a selective inhibitor of PI3K led
initially to INCB04009311 (3, dezapelisib). Dezapelisib (3) was
advanced into clinical trials for the treatment of patients with
previously treated B-cell malignancies.12 Even though these
compounds demonstrate proof-of-concept that inhibition of
PI3Ks are effective in treating cancer, the clinical trials of 1, 2,
and 3 all revealed similar liver toxicity that have limited their
full potential and there remains a need to develop alternative
inhibitors with better safety profiles.13-15
substitution (5) dramatically improved the potency of 4 (IC50
=
8.4 nM vs 430 nM). Compound 5 was similarly potent to 3 but
the low free fraction in human plasma of 5 translated into a PBadj
IC50 in the Pfeiffer assay that was 15-fold less potent than 3.
Introducing more polarity to the quinoline ring with the addition
of one nitrogen at the 2-position of quinoline 5 gave cinnoline
6. Compound 6 displayed better human plasma free fraction,
higher Caco2 permeability (Supporting Information, Table
S15), and similar potency compared with 5. While 6 still
exhibited a higher PBadj IC50 in the Pfeiffer assay compared with
3, this was offset with improved rat PK that revealed an increase
in oral exposure (AUC of 13 M*h (6) vs AUC of 4.4 M*h
(3) for same dose of 5 mg/kg). Even though the potency of 6
was weaker compared with 3, the improvements in PK with 6
warranted further advancement. Unfortunately, 6 exhibited
toxicity when dosed in dogs and its progression was halted.
Dezapelisib (3) is a potent inhibitor of PI3K (IC50 = 3.4 nM)
with very good selectivity over the other isoforms of PI3K and
over 200 other kinases,11 and it displayed cellular activity in
SU-DHL-6 viability (IC50 = 18 nM) and Pfeiffer proliferation
(IC50 = 14 nM) assays (Table 1). To estimate the clinical plasma
concentration (total drug) needed to achieve half maximal
inhibitory concentration (IC50), the IC50 value from the Pfeiffer
cell assay was corrected for the fraction unbound in media to
approximate IC50, and then corrected for the fraction unbound
in human plasma. The calculated protein binding adjusted
(PBadj) IC50 in the Pfeiffer assay further supported 3 was indeed
a potent inhibitor of PI3K.
The pharmacokinetic (PK) studies of 3 in cynomolgus
monkey (cyno) demonstrated that 3 exhibited good oral
exposure (AUC of 4.9 M*h dosed at 10 mg/kg), but also had
a short half-life (1.3 h). Improvements in potency, PK, and
toxicity were the goals of a second-generation inhibitor of
PI3K As a result of the encouraging properties outlined
above, 3 provided a good starting point to explore structurally
diverse scaffolds. These studies culminated with the design of
Unsuccessful attempts to find alternative bicyclic cores with
better potency or properties as the cinnoline led to the design of
inhibitors that featured a monocyclic core ring instead of a
bicyclic ring. Opening the pyridazine ring of cinnoline 6
(Figure 3) and installing a cyano group at the 3-position of the
resultant phenyl ring provided 7. While 7 was less potent than
6 toward PI3K in binding and cellular assays, structure–
activity relationship (SAR) studies revealed that replacement of
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the cyano group in 7 with a heteroaryl group could impact
potency significantly. The methylpyrazole group of 8 afforded
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improved potency in binding and cellular assays compared with
7. Although 8 was very potent, two aromatic groups adjacent
to each other
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Figure 3. Monocyclic purine inhibitors 7-11.
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on the phenyl ring was believed to be less than ideal for
achieving the physical properties needed for a drug candidate.
SAR studies at the 2-position of the phenyl ring revealed that
the solvent exposed 3-fluorophenyl group could be significantly
simplified to the methoxy ether 9 without loss of potency in the
enzyme binding assay.
Figure 4. Evolution of purine inhibitor 11 to
aminocyanopyrimidine inhibitors 12 and 13 to
pyrazolopyrimidine inhibitors 14 and 15.
Truncating the phenyl group to methoxy at the 2-position
enabled an expanded examination of SAR at the 3-position.
Substitution of the pyrazole ring for the sulfonyl phenyl analog
10 afforded similar potency with acceptable Caco2
permeability and human intrinsic clearance (hIntCl) values
(Supporting Information, Table S15). Unfortunately, 10 had
low free fraction in human plasma which translated into a very
high PBadj IC50 in the Pfeiffer assay (IC50 = 3100 nM). The more
polar pyridyl analog 11 provided a 9-fold improvement in
human plasma free fraction compared with 10. The oral
exposure of 11 in rat PK was not as good as 6 (AUC of 13 M*h
(6) vs AUC of 3.0 M*h (11) for same dose of 5 mg/kg) which
could have been caused by the low Caco2 permeability (0.5 x
10-6 cm/s) of 11. While many analogs were prepared in this
series, finding the right balance of properties remained a
challenge. Using the monocyclic phenyl core, alternative
hinge-binders were considered as a potential solution.
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carboxamides. The dimethyl amide found in 13 provided the
best combination of potency and physical properties with
decreased HEK293 and hERG levels. Amide 13 exhibited good
oral exposure in rat PK (AUC of 7.7 M*h dosed at 4 mg/kg)
and was advanced into cyno PK where it surprisingly showed a
very short half-life (0.2 h) and very poor oral exposure (AUC
of 0.2 M*h dosed at 2 mg/kg). A number of other compounds
that contained the aminocyanopyrimidine hinge-binder also
exhibited poor cyno PK. Metabolic studies revealed that the
aminocyanopyrimidine hinge-binder was susceptible to
oxidation in cynos by aldehyde oxidase (AO) at the 2'-position.
The aminocyanopyrimidine was abandoned and the focus
shifted back to hinge-binder optimization.
It was reasoned that blocking the 2'-position of the
pyrimidine ring could prevent AO oxidation. Unfortunately, a
variety of functional groups that were examined resulted in
either loss of potency or compounds that did not have optimal
ADME properties (data not shown). Several other monocyclic
and bicyclic hinge-binders were examined and the most
promising was the pyrazolopyrimidine of 14 which was
essentially a cyclized version of the aminocyanopyrimidine
(Figure 4). The potency of 14 could be substantially improved
with the addition of a methyl group at the 3'-position of the
pyrazolopyrimidine (15) which resulted in a >100-fold increase
in PI3K inhibition. The overall profile of 15 appeared
encouraging and SAR studies at the 3-position of the central
phenyl ring continued with aryl groups. However, a parallel
effort to identify saturated rings at the 3-position had initiated
The purine hinge-binder was replaced with 4,6-
diaminopyrimidine-5-carbonitrile (Figure 4), which proved to
be an effective substitute. Compound 12 offered a slight
enhancement in potency compared with 11 but also a large
improvement in Caco2 permeability (7.9 vs 0.5 x 10-6 cm/s).
Taken together these properties delivered excellent oral
exposure in rat PK (AUC of 10 M*h dosed at 4 mg/kg) for 12.
Unfortunately, 12 had elevated levels of inhibition in the
HEK293 and hERG counter screens (Supporting Information,
Table S14). The strategy to reduce HEK293 and hERG
inhibition with polar amide groups resulted in the examination
of a variety of pyridyl
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and, in general, provided compounds with better physical IC50 in the Pfeiffer assay as cyano 21, but with slightly better
Caco2 permeability (1 x 10-6 cm/s), offered the best balance of
properties. Compound 20 was selected for further profiling
which revealed it is potent in the PI3K filter binding assay and
is very selective over the other PI3K isoforms (Table 3). In
addition, 20 exhibits selectivity over a panel of 197 kinases20
and is very potent in the RAMOS cellular and human whole
blood basophil assays. Compound 20 did not inhibit hERG or
the major isoforms of human cytochrome P450, and it has very
good solubility at pH 7.4 (see Supporting Information, Table
S13, for additional data).
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properties.
A number of saturated rings were synthesized and selected
examples are shown in Figure 5. Excitingly, piperidine 16 was
only slightly less potent than pyridyl amide 15 with a similar
intrinsic clearance, but 16 had a higher free fraction in human
plasma. Azetidines typically had a better profile than
piperidines and extensive SAR studies led to azetidine 17.
Compound 17 was very potent in the biochemical and cellular
assays and it had a very high free fraction in human plasma that
translated into a PBadj IC50 in the Pfeiffer assay that was 18-fold
more potent than 3. Compound 17 was studied in rat and cyno
PK where it exhibited good oral exposure in rats (AUC of 6.8
M*h dosed at 5 mg/kg) but only moderate oral exposure in
cyno (AUC of 4.1 M*h dosed at 1 mg/kg). Initial toxicology
studies indicated 17 was tolerated in dogs but, unfortunately,
the 28-day investigational new drug (IND)-enabling toxicology
study revealed testicular lesions which halted further
development.
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One challenge observed with saturated heterocycles
containing a basic nitrogen was their propensity to inhibit
hERG. This could be mitigated with nearby polar groups such
as the secondary alcohol found in 17. Another approach to
mitigate hERG inhibition was to remove the basic nitrogen
altogether which led to the design of the five-membered lactam
ring of 18. As the result of reduced hERG inhibition and similar
potency to 17, lactam 18 was deemed to be a good lead for
further investigation and several analogs (18-25) were
synthesized (Supporting Information, Schemes S13 – S16).
Both diastereoisomers of the lactam ring provided compounds
that were potent, although the lactam stereogenic center was
usually not assigned. The more potent of the lactam
diastereoisomers are presented in Table 2 (18-21). The
corresponding less potent diastereoisomers (22-25) can be
found in the Supporting Information.
Figure 6. Proposed binding model of 20 (orange) with PI3K
overlaid with 3 (cyan).
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The modeling of 20 with PI3K (Figure 6), which was based
on the X-ray co-crystal structure (PDB ID 6G6W) of a different
inhibitor with PI3K,21 revealed a similar induced fit exhibited
by other PI3K-selective inhibitors.22 The pyrazolopyrimidine
in 20 binds the hinge region of PI3K forming hydrogen bonds
with the NH of Val828 and CO of Glu826. The phenyl ring is
positioned in the induced specificity pocket formed by the side
chains of Trp760 and Met752, which adopts this alternate
conformation to accommodate the phenyl ring. The chloro and
fluoro groups on the phenyl ring of 20 effectively mimic the
second ring commonly found in the bicyclic core structure of
PI3K inhibitors (e.g., 3). The carbonyl of the lactam also
forms hydrogen-bonding interactions with both Thr750 and
Lys708.
SAR studies of the lactam series focused around the central
phenyl ring. Converting the methoxy of 18 to ethoxy (19)
resulted in a slight increase in potency. Replacement of the
methyl at the 4-position of 19 with fluoro (20) resulted in
another small boost in potency. The most potent analog was
cyano 21 which was about 3-fold more potent in the cellular
assays than
The PK of 20 have been studied in rats, dogs, and monkeys
(Supporting Information, Table S20). Following intravenous
(IV) administration, 20 displayed low systemic clearance,
representing 26%, 2%, and 5% of the hepatic blood flow in rats,
dogs, and monkeys, respectively. The steady-state volume of
distribution was moderate in rats (1.54 L/kg) and monkeys (0.72
L/kg), but low in dogs (0.32 L/kg). The terminal elimination
half-life values were favorable after IV dosing, ranging from
4.0 h (rat) to 7.3 h (monkey) with similar values obtained after
oral dosing. Following oral administration 20 was rapidly
absorbed with Tmax (time taken to reach the maximum
concentration) values of 0.3 h (rat) to 2.5 h (monkey). Oral
exposure was high and the bioavailability of 20 was complete
in dogs (100%), and high in monkeys (79%) and rats (74%).
Figure 5. Monocyclic pyrazolopyrimidine inhibitors 16-18
with 3-substituted saturated cyclic rings.
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19. The intrinsic clearance of these lactams were all very
similar. The cyano analog (21) had the highest free fraction
(23%), however, it also had the lowest Caco2 permeability (0.3
x 10-6 cm/s). The fluoro analog (20), which had the same PBadj
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model revealed inhibition of the phosphorylation of AKT at
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Ser473.
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To determine the effects of 20 in vivo, the Pfeiffer DLBCL
subcutaneous mouse xenograft model was used. Pfeiffer cells
are highly sensitive to PI3Kδ inhibition in vitro with IC50 values
for 20 in proliferation and signaling assays less than 5 nM.20
Compound 20 dosed orally twice daily significantly inhibited
Pfeiffer xenograft tumor growth at 1 mg/kg (Figure 7A;
p<0.05)). This correlated with profound inhibition of the
phosphorylation of AKT at Ser473, a marker of PI3Kδ activity,
observed in mice (Figure 7B). Descriptions of additional
pharmacologic, pharmacokinetic, and pharmacodynamic
analyses in multiple models are described elsewhere.20
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Preclinical 28-day IND-enabling toxicology studies in rats
and dogs demonstrated no liver toxicities and suggested 20 was
suitable for advancement into clinical trials. Thus far, 20 has
shown reduced liver-related toxicities in clinical trials,23 which
supports the hypothesis that the hepatotoxicity displayed by 1,
2, and 3 could be related to the purine group that is common to
all three first-generation compounds.20
In summary, a potent and selective inhibitor of PI3K was
discovered. The bicyclic thiazolopyrimidinone core of 3 could
be truncated to a single phenyl ring. Replacement of the purine
hinge-binder of
3
with pyrazolopyrimidine provided
compounds that were slightly more potent with improved
cellular permeability. Further optimization revealed the five-
membered lactam ring was a good replacement of aryl rings at
the 3-position of the core phenyl ring that led to the discovery
of 20. The excellent pharmacokinetics of 20 in various species,
its efficacy in inhibiting tumor growth in a Pfeiffer xenograft
model, and its lack of preclinical toxicity allowed it to be
advanced into clinical development. Parsaclisib (20) is
currently in Phase 2 clinical trials for the treatment of various
cancers.16-19
Figure 7. (A) Compound 20 suppresses tumor growth in
Pfeiffer mouse xenograft model. Compound 20 was
administered orally twice daily for 14 days. The percentage of
tumor growth inhibition (TGI) was measured on the final day
of study. (B) Analysis of mice from the Pfeiffer xenograft
Table 1. Selected SAR of 3-17
% fu in
human
plasma
SU-DHL-6
Viability
IC50 (nM)
Pfeiffer
Proliferation
IC50 (nM)
Pfeiffer
PBadj IC50
(nM)
PI3K SPA
IC50 (nM)
Cmpd
3
4a
3.4
430
8.4
13
18
1800
140
73
14
490
50
66
3200
1000
270
ND
ND
950
3100
40
17
10
5
1.4
5.9
0.64
ND
2.9
1.3
12
6
26
7a
8a
1300
60
99
660
8.7
120
130
9.5
3.4
17
5.3
2.8
3.6
1.7
0.99
1.8
120
0.93
11
9
100
170
14
10
11
12
13
14a
15
16a
17
3.1
21
17
14
61
22
840
7.4
44
610
8.6
11
4500
61
9.2
8.9
19
53
1.9
2.4
1.5
3.6
42
aRacemates; bdosed at 4 mg/kg or dose adjusted to 4 mg/kg; fu = fraction unbound; ND = not determined.
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Table 2. SAR of Lactam Pyrazolopyrimidines 18-21
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% fu in
human
plasma
SU-DHL-6
Viability
IC50 (nM)
Pfeiffer
Proliferation
IC50 (nM)
Pfeiffer
PBadj IC50
(nM)
IntCL
(L/h/kg)
Caco2 Pm
PI3K SPA
Cmpda
*
R
R’
(x10-6 cm/s)
IC50 (nM)
Me
Me
F
Me
Et
13
2.1
0.7
0.7
0.7
0.7
2.8
1.9
1.0
0.3
18
19
20
21
2.4
1.4
51
4.8
2.5
1.7
480
47
10
6.5
5.8
23
R
Et
1.6
<1.0
<1.0
4.2
4.1
CN
Et
0.47
aSingle isomers; bdosed at 4 mg/kg or dose adjusted to 4 mg/kg; fu = fraction unbound.
Table 3. Summary of InVitro Profile of 20
Assay
Result
<1.0
1.1 ± 0.50 11
N
7
PI3K SPA IC50 (nM)
PI3K FB IC50 (nM)
PI3K FB IC50 (nM)
PI3K FB IC50 (nM)
PI3K FB IC50 (nM)
SU-DHL-6 IC50 (nM)
Pfeiffer IC50 (nM)
>20,000
>20,000
>10,000
4
4
5
1.6 ± 0.90 22
2.5 ± 0.65
1.1 ± 0.85 11
8
RAMOS IC50 (nM)
WB IC50 (nM)
2.0 ± 1.2
75,000
5
1
3
hERG patch IC50 (nM)
Solubility at pH 7.4 (g/mL)
210 ± 72
■ ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: XXXX. Experimental protocols and
characterization data (PDF).
■ AUTHOR INFORMATION
Corresponding Author
*E-mail: eddyyue@incyte.com
Current affiliations: P. A. S. and A. P. C., Prelude Therapeutics, Inc., Wilmington, DE, USA; B. M., private consultant, Moraga, CA, USA
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ORCID
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Eddy W. Yue: 0000-0001-9554-5078
Andrew P. Combs: 0000-0003-1418-5168
Author Contributions:
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



Design/conception of study or data acquisition/analysis and/or interpretation: all authors
Drafting manuscript or providing critical review of content: all authors
Approval of final draft for publication: all authors
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Accountable for all aspects of work: all authors
Funding Sources: Incyte Corporation, Wilmington, DE, USA
■ ACKNOWLEDGMENTS
This manuscript is dedicated to the memory of our friend and colleague Dr. Yun-Long Li. Yun-Long was a passionate and creative
medicinal chemist who initiated the PI3K program and led the team that identified INCB040093. The discovery of parsaclisib could not
have been possible without the pivotal insights from Yun-Long.
We thank Laurine Galya, Mei Li, James Doughty, and Karl Blom for their analytical assistance. We thank Ravi Jalluri for creating the
molecular modeling graphics. We thank Jordan Fridman for discussions related to pharmacology. We thank Daniel Levy, Neil
Lajkiewicz, and Matthew McCammant for proofreading this manuscript. Medical writing assistance was provided by Simon J. Slater,
PhD, CMPP, of Envision Pharma Group (Philadelphia, PA), funded by Incyte Corporation.
■ ABBREVIATIONS
ADME, absorption, distribution, metabolism, and excretion; AKT, protein kinase B; AUC, area under the plasma drug concentration–time
curve; Cmax, maximum drug concentration; F, fraction of an administered dose of unchanged drug that reaches the systemic circulation;
FB, filter binding; hERG, human ether-a-go-go-related gene; IV, intravenous; mTOR, mammalian target of rapamycin; SPA, scintillation
proximity assay; t1/2, time taken for half the initial dose of medicine administered to be eliminated from the body; Vdss, volume of
distribution at steady state; WB, whole blood.
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